S1P1 Threonine 236 Phosphorylation Mediates the Invasiveness of Triple-Negative Breast Cancer and Sensitivity to FTY720.
Cells
; 12(7)2023 03 23.
Article
in En
| MEDLINE
| ID: mdl-37048053
ABSTRACT
Hyperactive sphingosine 1-phosphate (S1P) signaling is associated with a poor prognosis of triple-negative breast cancer (TNBC). Despite recent evidence that links the S1P receptor 1 (S1P1) to TNBC cell survival, its role in TNBC invasion and the underlying mechanisms remain elusive. Combining analyses of human TNBC cells with zebrafish xenografts, we found that phosphorylation of S1P receptor 1 (S1P1) at threonine 236 (T236) is critical for TNBC dissemination. Compared to luminal breast cancer cells, TNBC cells exhibit a significant increase of phospho-S1P1 T236 but not the total S1P1 levels. Misexpression of phosphorylation-defective S1P1 T236A (alanine) decreases TNBC cell migration in vitro and disease invasion in zebrafish xenografts. Pharmacologic disruption of S1P1 T236 phosphorylation, using either a pan-AKT inhibitor (MK2206) or an S1P1 functional antagonist (FTY720, an FDA-approved drug for treating multiple sclerosis), suppresses TNBC cell migration in vitro and tumor invasion in vivo. Finally, we show that human TNBC cells with AKT activation and elevated phospho-S1P1 T236 are sensitive to FTY720-induced cytotoxic effects. These findings indicate that the AKT-enhanced phosphorylation of S1P1 T236 mediates much of the TNBC invasiveness, providing a potential biomarker to select TNBC patients for the clinical application of FTY720.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Triple Negative Breast Neoplasms
/
Fingolimod Hydrochloride
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Sphingosine-1-Phosphate Receptors
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Animals
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Humans
Language:
En
Journal:
Cells
Year:
2023
Document type:
Article
Affiliation country:
United States
Country of publication:
CH
/
SUIZA
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SUÍÇA
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SWITZERLAND